The complement system plays a central role in the clearance of immune complexes and the immune response to infectious agents, foreign antigens, virus-infected cells and tumor cells. However, complement is also involved in pathological inflammation and in autoimmune diseases. Therefore, inhibition of excessive or uncontrolled activation of the complement cascade could provide clinical benefit to patients with such diseases and conditions.
The complement system encompasses two distinct activation pathways, designated the classical and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R. R. Rich, Mosby Press; 1996, 363-391). The classical pathway is a calcium/magnesium-dependent cascade which is normally activated by the formation of antigen-antibody complexes. The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g. cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials). Activation of the complement pathway generates biologically active fragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxins and C5b-9 membrane attack complexes (MAC), which mediate inflammatory activities involving leukocyte chemotaxis, activation of macrophages, neutrophils, platelets, mast cells and endothelial cells, vascular permeability, cytolysis, and tissue injury.
Factor D is a highly specific serine protease essential for activation of the alternative complement pathway. It cleaves factor B bound to C3b, generating the C3b/Bb enzyme which is the active component of the alternative pathway C3/C5 convertases. Factor D may be a suitable target for inhibition, since its plasma concentration in humans is very low (1.8 μg/ml), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P. H. Lesavre and H. J. Müller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J. E. Volanakis et al., New Eng. J. Med., 1985; 312: 395-401).
The down-regulation of complement activation has been demonstrated to be effective in treating several disease indications in animal models and in ex vivo studies, e.g. systemic lupus erythematosus and glomerulonephritis (Y. Wang et al., Proc. Natl. Acad. Sci.; 1996, 93: 8563-8568), rheumatoid arthritis (Y. Wang et al., Proc. Natl. Acad. Sci., 1995; 92: 8955-8959), cardiopulmonary bypass and hemodialysis (C. S. Rinder, J. Clin. Invest., 1995; 96: 1564-1572), hyperacute rejection in organ transplantation (T. J. Kroshus et al., Transplantation, 1995; 60: 1194-1202), myocardial infarction (J. W. Homeister et al., J. Immunol., 1993; 150: 1055-1064; H. F. Weisman et al., Science, 1990; 249: 146-151), reperfusion injury (E. A. Amsterdam et al., Am. J. Physiol., 1995; 268: H448-H457), and adult respiratory distress syndrome (R. Rabinovici et al., J. Immunol., 1992; 149: 1744-1750). In addition, other inflammatory conditions and autoimmune/immune complex diseases are also closely associated with complement activation (V. M. Holers, ibid., B. P. Morgan. Eur. J. Clin. Invest., 1994:24:219-228), including thermal injury, severe asthma, anaphylactic shock, bowel inflammation, urticaria, angioedema, vasculitis, multiple sclerosis, myasthenia gravis, membranoproliferative glomerulonephritis, and Sjögren's syndrome.
Age-related macular degeneration (AMD), when left untreated, is the leading cause of irreversible blindness in people 50 years of age or older in the developed world (Friedman et al., Arch Opthalmol, 122:564-72 (2004)). Approximately 8 million Americans have an intermediate stage of AMD (characterized by the presence of large-sized drusen in the macula (center of the retina)), placing them at risk for developing advanced disease and vision loss. Advanced AMD is classified into two clinical forms: geographic atrophy (GA) and an exudative or wet form characterized by choroidal neovascularization (CNV) (Age-Related Eye Disease Study [AREDS] Research Group, Arch Ophthalmol, 121:1621-24 (2003)). GA refers to confluent areas of retinal pigment epithelial (RPE) cell death accompanied by overlying photoreceptor atrophy. GA has a substantial impact on visual function: approximately 40% of a subset of patients has been shown to lose at least 3 Snellen equivalent lines of vision over 2 years (Sunness et al., Retina, 7:204-10 (2007)). Although the etiology of AMD is largely unknown, age, smoking ethnicity, diet and genetics have been suggested to be risk factors in AMD (Amabti et al., Surv Opthalmol, 48(3): 257-93 (2003); Gorin et al., Mol Aspects Med, 33:467-486 (2012)) and the alternative complement pathway (ACP) have been implicated in AMD (de Jong, N. Engl J. Med., 355: 1474-1485 (2006)). Increased activation of ACP has been found in drusen, lipoproteinous depositions in the space between the RPE and Bruch's membrane, which are a hallmark of AMD. Moreover, a role for ACP activation in AMD has been supported by human genetics (Yates et al., New Engl J Med, 357: 553-61 (2007)). Complement factor D is a rate-limiting enzyme that plays a pivotal role in the activation of the alternative complement pathway (ACP). Evidence for factor D in the pathogenesis of AMD includes protection against oxidative stress-mediated photoreceptor degeneration in a murine model with genetic deficiency of factor D (Rohrer et al., Invest Ophtalmol Vis Sci, 48:5282-89 (2007)) and detection of increased systemic activation of complement, including factor D, in the serum of AMD patients versus controls, suggesting that AMD may be a systemic disease with local manifestations in the aging macula (Scholl et al., PLos ONE, 3(7):e2593 (2008)). Moreover, multiple papers on the genetics of AMD have independently confirmed a single nucleotide polymorphism in complement factor H(CFH). Y402H that was strongly linked to increased risk of developing both early and late AMD (Edwards et al., Science, 308(5720): 421-4 (2005); Hageman et al., PNAS, 102(20): 7227-32 (2005); Haines et al., Science, 208(5720): 419-21 (2005); Klein et al., Science, 308(5720): 385-9 (2005); Prosser et al., J. Exp. Med., 204(10: 2277-83 (2007); Zareparsi et al., Am J. Hum Genet, 77:149-153 (2005)). Other risk alleles include polymorphisms in a complement factor H(CFH) risk locus (rs10737680), in a complement factor I (CFI) risk locus (rs4698775), in a complement component 2/complement factor B (C2/CFB) risk locus (rs429608), and in a complement component (C3) risk locus (rs2230199) (Fritsche et al., Nat Genet, 45:433-439 (2013)). CFI, CFH, C2, CFB and C3 are additional members of the complement pathway. Additional SNPs associated with genes in the complement pathway and their correlation with AMD have been implicated in, e.g., PCT publications WO2011/017229, WO2009/146204 and WO2009/134709. None of these references, however, disclosed or suggested correlation of the identified SNPs with how the patient's disease progresses over time or how well the patient responds to AMD therapy. In a prospective study of genetic effects on AMD progression, genetic variants such as SNPs in the complement pathway were associated with progression from intermediate drusen to large drusen and from large drusen to GA or NY. Yu et al., Invest. Ophthalm. & Visual Sci., 53:1548-56 (2012). The results suggest that genes associated with AMD may be involved in transitions between distinctly different AMD stages during progression. It was not known, however, whether the identified genes are associated with rate of disease progression, e.g., within an advanced stage such as GA.
Currently, anti-VEGF (vascular endothelial growth factor) is the standard of care for treatment of most cases of the wet from of advanced AMD. There is currently no effective treatment that halts or slows the progression of GA. There is no approved treatment to prevent progression of GA, creating a significant unmet need for patients with GA. Thus, there is a need to identify efficacious therapies for GA and improved methods for understanding how to treat GA patients. Specifically, diagnostic methods useful for identifying patients at risk for increased GA progression rate and likely to benefit from anti-factor D antibody treatment would greatly benefit clinical management of these patients. This invention meets these and other needs.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety for any purpose.